PubMed Health⌕ Search

Biomedical subjects

J L Way

Publications and source records attributed to J L Way.

16 recordsLinked to original sources
PubMed1992

Antagonism of the lethal effects of cyanide with resealed erythrocytes containing rhodanese and thiosulfate.

A new concept has been presented for the antagonism of cyanide and possibly other chemical toxicants. Until now, only a half dozen truly specific "antidotes" were known. There are many other "antidotes" which merely prevent the absorption or enhance the elimination of a toxic compound rather than specifically destroying the substance to prevent its toxic effect. This new approach has considerable conceptual significance in toxicology, as it suggests the encapsulating other enzymes to degrade various other chemical toxicants. There are many chemical toxicants for which there are no specific antidotes, and the conceptual approach of employing erythrocyte-encapsulated enzyme provides an innovative, specific approach to antagonize the toxic and lethal effects of these chemicals.

Animals↗
PubMed1991

In vivo studies on rhodanese encapsulation in mouse carrier erythrocytes.

Resealed erythrocytes containing sodium thiosulfate and rhodanese (CRBC) are being employed as a new approach in the antagonism of cyanide intoxication. In earlier in vitro studies, the behavior of red blood cells containing rhodanese and sodium thiosulfate was investigated with regard to their properties and their capability of metabolizing cyanide to thiocyanate. The present studies are concerned with the properties of these rhodanese-containing carrier erythrocytes in the intact animal. These carrier erythrocytes were administered intravenously and the survival of the encapsulated enzyme was compared with the administration (iv) of free exogenous enzyme. Also, the amount of leakage of the encapsulated rhodanese from the red blood cell was determined. The survival of the carrier red blood cell. prepared by hypotonic dialysis, was found to be characterized by a biphasic curve. There was an initial rapid loss of approximately 40 to 50% of the carrier cells with a t1/2 = 2.5 hr. Subsequently the remaining resealed annealed carrier erythrocytes persisted in the vascular system with a t1/2 = 8.5 days. When free exogenous rhodanese was administered directly into the vascular system, it was rapidly eliminated with a t1/2 = 53 min. Red blood cells containing sodium thiosulfate and rhodanese apparently are effective in vivo in the biotransformation of cyanide. In animals pretreated with encapsulated rhodanese and sodium thiosulfate, blood cyanide concentrations are appreciably decreased with a concomitant increase in thiocyanate ion, a metabolite of cyanide. When erythrocytes, which contained no rhodanese or sodium thiosulfate, were subjected to hypotonic dialysis, cyanide was not metabolized to any appreciable extent. Furthermore, carrier erythrocytes containing rhodanese and sodium thiosulfate were found to increase the protection against the lethal effects of cyanide by approximately twofold. The ability of these carrier erythrocytes alone to metabolize cyanide and to antagonize the lethal effects of cyanide reflects the potential of this new antidotal approach in the antagonism of chemical toxicants.

Animals↗
PubMed1991

Rhodanese and sodium thiosulfate encapsulated in mouse carrier erythrocytes. II. In vivo survivability and alterations in physiologic and morphologic characteristics.

Biodegradable drug carrier mechanisms were employed in drug antagonism studies. Prior studies indicated that erythrocytes containing encapsulated rhodanese and sodium thiosulfate metabolized cyanide to thiocyanate in vitro. Studies were conducted to investigate the properties of these sulfurtransferase-loaded red blood cells in vivo by administering the carrier red blood cells intravenously. Approximately 40 to 50% of the cells were eliminated within the first few hours while the remaining loaded erythrocytes persisted in the circulation. The present studies were initiated to investigate the characteristics of the disposition of the loaded erythrocytes and to examine differences in the properties between carrier and noncarrier erythrocytes. Also, the disposition and viability of the erythrocytes in vivo were studied with relation to various biochemical, physiological, and morphological properties. These studies indicated that the carrier erythrocytes had a smaller cell volume and were more susceptible to hemolysis than normal erythrocytes. Morphologic studies by electron microscopy indicated that extensive morphologic changes occurred during the procedures after hypotonic dialysis, isotonicity adjustment, and resealing were completed. Differences were noted between those cells that were only resealed and those cells that were also subjected to annealing. The morphologic characteristics of most of the cells were restored to the "normal" morphologic appearance only after annealing. Annealed erythrocytes' in vivo survivability was correlated with the physical properties of these cells.

Animals↗
PubMed1979

Cyanide intoxication in sheep: enhancement of efficacy of sodium nitrite, sodium thiosulfate, and cobaltous chloride.

For treatment of cyanide intoxication of ruminants, the present recommended doses of sodium nitrite (5 mg/kg of body weight) and sodium thiosulfate (25 to 50 mg/kg) are smaller than those recommended for other animals; the decrease is partially attributed to the greater susceptibility of ruminants to the toxic effects of sodium nitrite. Based on the high tissue concentration and activity rate of rhodanese in ruminants, sulfur donors such as sodium thiosulfate could be utilized more efficaciously. Doses of sodium nitrite and sodium thiosulfate (up to 22 and 660 mg/kg, respectively) were evaluated in the present studies. Adjustment of the antidotal combination provided almost three times the protection afforded by the previously recommended doses. Moreover, under the conditions tested, the newly adjusted dose levels of sodium thiosulfate alone were more effective than the previously used antidotal combination of sodium nitrite and sodium thiosulfate and this protective effect was enhanced by cobaltous chloride (10.6 mg/kg) or sodium nitrite. The present recommended therapeutic approach to cyanide intoxication in sheep should be based primarily on administration of a much higher dose of sodium thiosulfate in combination with sodium nitrite or cobaltous chloride (or both).

Animals↗
PubMed1977

Cyanide intoxication in sheep: therapeutic value of oxygen or cobalt.

The combination of cobalt salts and oxygen with the traditional sodium nitrite-sodium thiosulfate antidote may have value as cyanide antidotes. Results reported previously in mice were extended to sheep in the present experiments. Cobaltous chloride (15 mg/kg of body weight) or oxygen with or without sodium nitrite and sodium thiosulfate were compared with respect to the median lethal dose of oral sodium cyanide. Although cobaltous chloride or oxygen used alone did result in a significant increase in the median lethal dose of sodium cyanide in sheep, the protection was minor compared with the overall protection provided by the classic antidotal combination of sodium nitrite and sodium thiosulfate. Cobaltous chloride combined with sodium nitrite and sodium thiosulfate did not provide any increase in protection more than that observed with sodium nitrite and sodium thiosulfate alone. Oxygen used in combination with sodium nitrite and sodium thiosulfate did significantly increase the protection. However, the increase in protection was not of sufficient magnitude to recommend it as a practicable addition to the present therapeutic regimen.

Animals↗
PubMed1975

A nuclear magnetic resonance study of nicotinamide adenine dinucleotide phosphate binding to Lactobacillus casei dihydrofolate reductase.

The binding of NADP+ to dihydrofolate reductase (EC 1.5.1.3) in the presence and absence of substrate analogs has been studied using 1H and 13C nuclear magnetic resonance (NMR). NADP+ binds strongly to the enzyme alone and in the presence of folate, aminopterin, and methotrexate with a stoichiometry of 1 mol of NADP+/mol of enzyme. In the 13C spectra of the binary and ternary complexes, separate signals were observed for the carboxamide carbon of free and bound [13CO]NADP+ (enriched 90% in 13C). The 13C signal of the NADP+-reductase complex is much broader than that in the ternary complex with methotrexate because of exchange line broadening on the binary complex signal. From the difference in line widths (17.5 +/- 3.0 Hz) an estimate of the dissociation rate constant of the binary complex has been obtained (55 +/- 10 sec-1). The dissociation rate of the NADP+-reductase complex is not the rate-limiting step in the overall reaction. In the various complexes studied large 13C chemical shifts were measured for bound [13CO]NADP+ relative to free NADP+ (upfield shifts of 1.6-4.3 ppm). The most likely origin of the bound shifts lies in the effects on the shieldings of electric fields from nearby charged groups. For the NADP+-reductase-folate system two 13C signals from bound NADP+ are observed indicating the presence of more than one form of the ternary complex. The IH spectra of the binary and ternary complexes confirm both the stoichiometry and the value of the dissociation rate constant obtained from the 13C experiments. Substantial changes in the IH spectrum of the protein were observed in the different complexes and these are distinct from those seen in the presence of NADPH.

Amides↗